This Mentored Patient-Oriented Research Career Development Award (K23) proposal outlines 5 years of training and research to equip the candidate to examine neurobehavioral and genetic aspects of mood disorders as an independent investigator. The candidate, Katherine M. Sharkey, MD, PhD, is a physician-scientist with a multidisciplinary background of sleep and circadian rhythms research and clinical training in psychiatry, internal medicine, and sleep medicine. This award provides Dr. Sharkey intensive training in genetics, advanced statistics, psychiatric research methods, and women's mental health. Training includes formal didactics, supervised hands-on tutorials, and mentored research. Principal mentor, Mary A. Carskadon, PhD, Director of the EP Bradley Hospital Sleep and Chronobiology Laboratory, oversees the training plan and mentors the candidate on biobehavioral measures (e.g., sleep). Co-mentors, Teri Pearlstein, MD, Director of Women and Infants' Hospital (WIH) Behavioral Health, and Caron Zlotnick, PhD, Director of Research for Women's Behavioral Health at WIH, provide clinical and research training in perinatal mood disorders. Co-mentors Valerie Knopik, PhD, Director, Division of Behavioral Genetics at Rhode Island Hospital, and John McGeary, PhD, Director, Providence VA Medical Center Molecular Genetics Laboratory, supervise the candidate's training in statistics and quantitative, molecular, and psychiatric genetics. The centerpiece of Dr. Sharkey's proposal is a prospective longitudinal study of mood, sleep, and genetic risk in perinatal women with a history of major depressive disorder or bipolar disorder. Sleep and mood are assessed in 125 women at 3rd trimester of pregnancy, and 2, 6, and 16 weeks postpartum. Participants undergo genotyping for theoretically selected serotonin and circadian clock gene polymorphisms. Data analyses use latent growth modeling, structural equation modeling, and Cox regression to examine associations between sleep, mood, and putative risk genetic polymorphisms. An important outcome of the project is to define a mood disorder intermediate phenotype: women who develop a postpartum mood episode related to their perinatal sleep changes. The proposed training prepares Dr. Sharkey for future work examining interactions of bioregulatory processes and genetic factors mediating mood regulation. This prospective approach examining perinatal sleep as a neurobehavioral trigger for mood episodes in genetically vulnerable women provides a framework for future studies of postpartum and other mood disorders. The line of inquiry in this proposal has clinical and public policy implications. Sleep disturbance may be a modifiable risk factor for development of a postpartum mood episode. If a subset of women is genetically vulnerable to postpartum sleep disturbance, innovative prevention and treatment strategies can be developed for those at highest risk. In the future, this work can be extended to include women without a psychiatric history. Evidence that sleep disturbance during the postpartum period impacts maternal mental health also provides support for initiatives to improve maternity leave and return-to-work policies. PUBLIC HEALTH RELEVANCE: Postpartum depression is the most common complication of childbirth; it has been linked to morbidity and mortality (including suicide) in new mothers, poor child outcomes, and high economic costs. This study examines whether postpartum depression is related to sleep changes after childbirth in a subgroup of women, and whether genetics play a role in who is at risk. If we find that changes in sleep around the time of childbirth increase the risk of postpartum depression in certain women, prevention and treatment strategies aimed at stabilizing sleep during pregnancy and the postpartum period can be developed.